1. Field of the Invention
The present invention concerns decreasing the melanin content in mammalian skin and hair by administering an effective melanin decreasing amount of one or more various derivatives of 5,6-dihydroxyindole (DHI) to a mammal, e.g., a human.
BACKGROUND INFORMATION
J. M. Pawelek and A. B. Lerner, "5,6-Dihydroxyindole Is A Melanin Precursor Showing Potent Cytotoxicity", Nature, 276, 627-628, (1978) shows that at high enough concentrations, the intermediates in melanin biosynthesis are toxic to cells producing pigment. The article also shows that 5,6-dihydroxyindole ("DHI") is far more toxic than L-dopa or tyrosine.
The intermediates in melanin biosynthesis are shown in FIG. 1 of J. M. Pawelek and M. Murray, "Increase in Melanin Formation and Promotion of Cytotoxicity in Cultured Melanoma Cells Caused By Phosphorylated Isomers of L-Dopa", Cancer Research, 46, 493-497, (1986). It is noted that in this FIG. 1 that DHI is synthesized from L-tyrosine or L-dopa in multiple reactions catalyzed by the enzyme tyrosinase. Tyrosinase is a key enzyme in pigment production and when it interacts with its various substrates (including DHI--see A. Korner and J. Pawelek, "Mammalian Tyrosinase Catalyzes Three Reactions in the Biosynthesis of Melanin", Science, 217, 1163-1165, (1982)) free radicals are produced with resultant toxicity to the cells.
Since pigment cells contain tyrosinase and other cells do not, this is likely the reason that the intermediates in melanin biosynthesis are selectively toxic to pigment cells.
The toxicity of melanin intermediates is also discussed in the following articles: J. Pawelek, A. Korner, A. Bergstrom and J. Bolognia, "New Regulators of Melanin Biosynthesis and the Autodestruction of Melanoma Cells", Nature, 286, 617-619, (1980) and J. M. Pawelek, "Factors Regulating Growth and Pigmentation of Melanoma Cells", J. Invest. Derm., 66, 201-209, (1976), J. McLane, M. Osber and J. M. Pawelek, "Phosphorylated Isomers of L-Dopa Stimulate MSH Binding Capacity and Responsiveness to MSH in Cultured Melanoma Cells", BBRC, 145, 719-725, (1987) shows that the effects are a matter of concentration.
DHI is highly unstable in the presence of oxygen and cannot be easily used in a cosmetic cream. It oxidizes into melanin spontaneously within a few minutes when exposed to air. Thus for it to be an effective depigmenting agent it must be derivatized to stabilize it.
European application 239,826 outlines methods for derivatizing DHI into compounds which are stable in air. EP 239,826 describes that derivatized DHI will be an effective pigmenting agent at concentrations from 0.01-15% wt/wt in various delivery compositions (see p. 5, bottom). There is no mention in EP 239,826 concerning depigmentation.
Depigmenting agents now commercially available are hydroquinone, used at 1-2% for OTC sales in products such as "PROCELANA" cream and 4% by prescription. Monobenzylether of hydroquinone is used by prescription in products such as "BENEQUIN" at 20%.